Method of inhibiting phenylethanolamine-n-methyltransferase

ABSTRACT

METHOD OF INHIBITING PHENYLETHANOLAMINE-N-METHYL TRANSFERASE BY THE ADMINISTRATION TO A HOST OF 2-AMINOBENZIMIDAZOLES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE 2-AMINOBENZIMIDAZOLES OF THIS INVENTION AS AN ACTIVE INGREDIENTS.

United States Patent ()ficc 3,629,475 Patented Dec. 21, 1971 3,629,475 METHOD OF INHlBlTlNG PHENYLETHANOLA- MlNE-N-METHYLTRANSFERASE Lewis R. Mandel, Edison, N.J., and Curt C. Porter, Glenside, Pa., assignors to Merck & (10., fine, Rahway, NJ. No Drawing. Continuation-impart of application Ser. No. 8,698, Feb. 4, 1970. This application Aug. 3, 1970, Ser.

Int. Cl. A61k 27/00 [1.5. Cl. 424-273 1 Claim ABSTRACT OF THE DISCLOSURE Method of inhibiting phenylethanolamine-N-methyl transferase by the administration to a host of Z-aminobenzimidazoles and pharmaceutical compositions containing the 2-aminobenzimidazoles of this invention as an active ingredient.

This application is a continuation-in-part of U.S. Ser. No. 8,698, filed Feb. 4, 1970, now abandoned.

This invention relates to pharmaceutical compositions. More specifically, this invention relates to new pharmaceutical compositions having as an active ingredient compounds having the following general formula:

wherein X is hydrogen, alkoxy, alkyl, haloloweralkyl, chloro or nitro; and Y is hydrogen, alkyl or chloro.

A final step in epinephrine biosynthesis is the transfer of a methyl group from S-adenosylmethionine to the amine nitrogen of norepinephrine. This step is catalyzed by phenylethanolamine-N-methyl transferase. This invention further relates to a method of inhibiting the formation of phenylethanolamine-N-methyl transferase utilizing the compounds of this invention, thereby resulting in a decrease in the formation of epinephrine.

These compounds have clinical utility in situations Where there is a selective overproduction of adrenal epinephrine such as in the treatment of narcotic addition, for example the management and control of morphine withdrawal, the treatment of various emotional states, for example anticipatory, painful and anxiety states in normal and psychiatric subjects, in particular, for the treatment of anxiety neurosis, and the prophylatic control of cardiovascular disorders characterized by increased heat rate and cardiac output, management of heart failure, cardiac shock or other situations in which stress exerts pressure upon cardiac performance, as for example, the management of myocardial infarctions.

The compounds constituting the active components of the compositions of this invention also are useful as fungicides and coccidiostats and may be used to treat diseases and conditions characterized by the presence of coccidia or fungi.

The compounds useful in the compositions of this invention may be prepared by Well-known prior art methods as, for example, by the procedures illustrated in 69 J. Am. Chem. Soc. 2459 (1947), 6 J. Med. Chem. 601 (1963), or 11 J. Med. Chem. 946 (1968).

A preferred embodiment of this invention is a method of inhibiting phenylethanolamine-N-methyl transferase which comprises the administration of a therapeutically effective amount of the compounds of the above formula to patients (animal or human). In general the daily dose can be from 0.05 mg./*kg. to 150 mg./kg. per day and preferably from 1 mg./kg. to 100 mg./kg. per day, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patients weight, general health, metabolism, age and other factors which influence response to the drug.

, Another embodiment of this invention is the provision of pharmaceutical compositions in dosage unit form which comprise from about 1 mg. to 500 mg. of a compound of the above formula.

The pharmaceutical compositions may be in a form suitable for oral use, for example, as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active benzimidazole ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraflin or olive oil.

Aqueous suspensions contain the active benzimidazoles in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturallyoccurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxy-cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan mono-oleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid parafiin. The only suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of Water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or Wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean lecithin, and esters of partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene soribtan mono-oleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and clixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1:3-butane diol.

The pharmaceutical compositions may be tableted or otherwise formulated so that for every 100 parts by Weight of the composition there are present between 5 and 95 parts by weight of the active ingredient and preferably between 25 and 85 parts by weight of the active ingredient. The dosage unit form will generally contain between about 100 mg. and about 500 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion it is apparent that the compositions of this invention can be administered orally or parenterally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques.

The following examples are presented to further i1- lustrate the invention:

EXAMPLE 1 A mixture of 250 parts of 5,6-dimethylbenzimidazole and 25 parts of lactose is granulated with suitable water, and to this is added 100 parts of maize starch. The mass is passed through a 16-mesh screen. The granules are dried at a temperature below 60 C. The dry granules are passed through a l6-rnesh screen, and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration.

4 EXAMPLE 2 A mixture of 50 parts of S-methoxybenzimidazole, 3 parts of the calcium salt of lignin sulphonic acid, and 237 parts of water is ball-milled until the size of the substantially all of the particles of benzyl ethyl sulfoxide is less than 10 microns. The suspension is diluted with a solution containing 3 parts of sodium carboxymethylcellulose and 0.9 part of the butyl ester of p-hydroxybenzoic acid in 300 parts of Water. There is thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes.

EXAMPLE 3 A mixture of 250 parts of 5,6-dichlorobenzimidazole, 200 parts of maize starch and 30 parts of alginic acid is mixed with a sufiicient quantity of a 10% aqueous paste of maize starch, and granulated. The granules are dried in a current of warm air and the dry granules are then passed through a 16-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oral administration.

EXAMPLE 4 A mixture of 500 parts of S-nitrobenzimidazole, parts of maize starch and 20 parts of gum acacia is granulated with a suflicient quantity of water. The mass is passed through a 12-mesh screen and the granules are dried in a current of warm air. The dry granules are passed through a 16-mesh screen, mixed with 5 parts of magnesium stearate and compressed into tablet form suitable for oral administration.

S-ethoxybenzimidazole, S-butoxybenzimidazole, S-ethylbenzimidazole, 5,6-diethylbenzimidazole, 5-propyl-6-ethylbenzimidazole, and S-chlorobenzimidazole may be compressed into tablet form suitable for oral administration by the above procedure.

What is claimed is:

1. A method of inhibiting the formation of phenylethanolarnine-N-methyl transferase comprising the administration to a patient in need of such treatment of a therapeutically effective amount of a compound of the formula:

/N Xv NHZ Y wherein X is hydrogen, chloro, loweralkoxy, haloloweralkyl or nitro; and Y is hydrogen, loweralkyl or chloro.

References Cited Joseph: .lour. Med. Chem., 6, p. 601 (1963). Grollman: Pharmacology & Therapeutics, 6th ed., pp. 

